2. In the name of GOD carnitine transporter deficiency
Dr.mohammad raza alaei
Pediatric Endocrinologist
Shahid beheshty university

3. carnitine transporter deficiency
also known as:
Systemic primary carnitine deficiency (SPCD)
carnitine uptake defect
systemic carnitine deficiency
Primary carnitine deficiency

4. carnitine transporter deficiency
Carnitine is an important amino acid for fatty acid metabolism
produced in the kidneys and liver
derived from meat and dairy products in the diet
essential role in the transfer of long-chain fatty acids into the mitochondria for beta-oxidation.

5. carnitine transporter deficiency
Biologic effects of low carnitine levels may not be clinically significant until they reach less than 10-20% of normal
(1-2% of normal)
carnitine transporter that is present in heart, muscle, and kidney
intracellular carnitine concentrations 20- to 50-fold higher than plasma concentration

6. Pathophysiology Carnitine deficiency may be primary or secondary
Primary carnitine deficiency:
is the only genetic defect
Mutations in the organic cation/carnitine transporter (OCTN2)
In defective carnitine transporter renal tubular cells unable to reabsorption carnitine prior to its excretion in urine

7. Pathophysiology
massively increased urine carnitine levels and significantly decreased plasma carnitine & Intracellular
carnitine impairs the entry of long-chain fatty acids into the mitochondrial matrix
impairs beta-oxidation and energy production, and the production of ketone bodies

8. Pathophysiology The 3 areas of involvement include
1)the cardiac muscle, (progressive cardiomyopathy) the most common form of presentation
2) the CNS, which is affected by encephalopathy caused by hypoketotic hypoglycemia
3) the skeletal muscle, which is affected by myopathy.

9. Pathophysiology
Muscle carnitine deficiency (restricted to muscle) is characterized by depletion of carnitine levels in muscle with normal serum concentrations
Evidence indicates that the causal factor is a defect in the muscle carnitine transporter.

10. Pathophysiology secondary carnitine deficiency :
metabolic disorders eg,urea cycle disease, organic acidemias
Preterm newborns
Valproic acid

11. Epidemiology Frequency: In Japanese study, 1 per 40,000 births
In Australia 1:37,000-1:100,000 newborns
Low levels of free carnitine can be identified in newborn screening
may reflect maternal primary carnitine deficiency

12. Epidemiology Mortality/Morbidity Sudden death Heart failure
Hypoglycemic Hypoketotic
encephalopathy
Race: 
Overall, this disorder is panethnic
Sex: No sex predilection

13. Epidemiology Age: onset ranging from 1 month to 7 years
Infants typically present with hypoketotic hypoglycemia
older children present with cardiomyopathy or skeletal myopathy

14. Signs and symptoms Primary carnitine deficiency
Muscle carnitine deficiency
Secondary carnitine deficiency

15. Signs and symptoms Primary carnitine deficiency
One classic initial presentation of is hypoketotic hypoglycemic encephalopathy, accompanied by hepatomegaly, elevated liver transaminases, and hyperammonemia
in the 1st yr of life
often preceded by metabolic stress such as extended fasting, infections or vomiting

16. Signs and symptoms
Cardiomyopathy ,most common presentation ,beginning at 1-4 yr
may occur with rapidly progressive heart failure
Pericardial effusion has also been observed in association with primary carnitine deficiency
Muscle weakness may accompany the heart failure or present by itself.

17. Signs and symptoms
Carnitine deficiency may be a cause of GI dysmotility, with recurrent episodes of abdominal pain and diarrhea
Hypochromic anemia
recurrent infections
Mild developmental delay can be the only manifestation in rare cases

18. Signs and symptoms
Maternal cases of SPCD have been identified at a higher than expected rate, often in women who are asymptomatic
Some mothers have also been identified through newborn screening with cardiomyopathy that had not been previously diagnosed

19. Signs and symptoms Although SPCD is an autosomal recessive condition
heterozygotes have been shown to be at an increased risk for developing benign cardiomyopathy

20. Signs and symptoms Muscle carnitine deficiency
Severe reduction in muscle carnitine levels and normal serum carnitine concentrations characterize muscle carnitine deficiency
restricted to muscle
no renal leak of carnitine or signs of liver involvement

21. Signs and symptoms Symptoms can appear in the first years
may occur later during the second or third decade
proximal muscular weakness of varying degree
exercise intolerance
myalgia

22. Signs and symptoms Secondary carnitine deficiency
Patients with organic acidemias
mitochondrial disorders
urea cycle defects
Renal Fanconi Tubulopathy
valproic acid
AIDS who are being treated with zidovudine

23. Diagnosis
In non-specific presentation : extremely low plasma carnitine level combined with an increased concentration of carnitine in urine the
newborn screening
confirmed by:
1)molecular testing
2)functional studies assessing the uptake of carnitine in cultured fibroblasts

24. treatment oral carnitine (100-200 mg/kg/day) is highly effective
correcting the cardiomyopathy and muscle weakness
As well as any impairment in fasting ketogenesis
Treatment continued for life

25. treatment very good outcomes for early treatment
Mothers who are identified after a positive newborn screen but are asymptomatic are typically offered carnitine supplementation as well
identification and treatment may prevent adult onset manifestations

26. Differential Diagnoses
· Cardiomyopathy, Dilated
· Heart Failure, Congestive
· Hyperammonemia
· Hypoglycemia
· Myoglobinuria
· Sudden Infant Death Syndrome

27. History
Carnitine deficiency most commonly as a secondary finding to other metabolic conditions
The first case of SPCD was reported in the 1980, in a child with fasting hypoketotic hypoglycemia
Later cases were reported with cardiomyopathy and muscle weakness
Newborn screening

28. Take home message hypoketotic hypoglycemic encephalopathy
Cardiomyopathy ,most common presentation ,beginning at 1-4 yr
Sudden Infant Death Syndrome
muscular weakness
valproic acid , zidovudine , RTA , premature

29. Thank you